PROJECT SUMMARY ABSTRACT Peripheral artery disease (PAD) is atherosclerotic disease with a decrease in blood flow to the arteries of the lower extremities. Exaggerated sympathetic nerve activity (SNA) and blood pressure (BP) are observed during intense exercise activity in this disease and these responses worsen exercise tolerance. The major goal of this proposal is to examine if heat exposure and heat treatment have beneficial effects on PAD. We will explore this clinically relevant hypothesis via examining the following specific aims utilizing both animal and human studies. 1. To examine the effects of heat exposure (i.e. whole body heating or local heating) on the exercise pressor reflex (EPR). We hypothesize that heat exposure attenuates amplified EPR in PAD. In human studies, muscle sympathetic nerve activity (MSNA) and BP responses to exercise will be examined during whole body heating or local muscle heating in PAD patients and healthy control subjects. We speculate that MSNA and BP responses will be accentuated in PAD patients as compared with healthy controls and these augmented responses will be significantly attenuated by heat exposure. In animal studies, renal SNA and BP responses to static muscle contraction will be examined in PAD rats and in control rats. We speculate that EPR will be enhanced in PAD rats and increasing muscle temperature by heat exposure will attenuate the amplified reflex. 2. To examine the engagement of temperature-sensitive P2X receptors in the effects of heat exposure on the EPR. We hypothesize that heat exposure decreases the levels of ATP in the muscle insterstitium and thereby attenuates amplification of the EPR in PAD. In animal studies, we speculate that heat exposure will attenuate the levels of interstitial ATP to a greater degree in PAD rats than in control rats. We further speculate that P2X subtype (i.e., P2X3) will play a role in regulating the EPR in PAD after heat exposure. 3. To examine the effects of heat treatment (i.e. a prior heat exposure) on BP response during walking in PAD patients and further to examine potential P2X mechanisms using animal studies. After a heat treatment, walking ability in PAD patients will be estimated on a treadmill with a Gardner protocol. We speculate that the BP response will be lower and the skeletal muscle oxygenation (SmO2) level will be higher than those without the heat treatment at the same stage of the walk protocol. Moreover, the heat treatment may increase peak treadmill walking time. In animal studies, we hypothesize that heat treatment attenuates expression, function and response of P2X3 in PAD. We will examine the protein expression levels of P2X3 in muscle afferent nerves of PAD rats. We speculate that heat treatment will decrease P2X3 in PAD rats. We further speculate that heat treatment will attenuate the amplification of P2X3 current amplitude in sensory neurons innervating muscle afferents in PAD rats and this thereby inhibits the exaggerated EPR.